Synthesis, modification, and evaluation of ( R)-de- O-methyllasiodiplodin and analogs as nonsteroidal antagonists of mineralocorticoid receptor

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 4; pp. 1171 - 1175
• Main Authors: Jiang, Cheng-Shi, Zhou, Rong, Gong, Jing-Xu, Chen, Li-Li, Kurtán, Tibor, Shen, Xu, Guo, Yue-Wei
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.02.2011; Elsevier
• Subjects: ( R)-De- O-methyllasiodiplodin; acetylation; Antagonist; antagonists; Biological and medical sciences; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - metabolism; Hormones. Endocrine system; inhibitory concentration 50; Macrolide; macrolides; Macrolides - chemical synthesis; Macrolides - chemistry; Macrolides - pharmacology; Medical sciences; Mineralocorticoid receptor; Mineralocorticoid Receptor Antagonists; mineralocorticoid receptors; Pharmacology. Drug treatments; Receptors, Glucocorticoid - antagonists & inhibitors; Receptors, Glucocorticoid - metabolism; Receptors, Mineralocorticoid - metabolism; Receptors, Progesterone - antagonists & inhibitors; Receptors, Progesterone - metabolism; Ring-closing-metathesis reaction; Structure-Activity Relationship; Two-Hybrid System Techniques; Antagonist; ( R)-De- O-methyllasiodiplodin; Mineralocorticoid receptor; Macrolide; Ring-closing-metathesis reaction; Ring size; Metathesis; Lactone; Oxygen heterocycle; Diphenols; In vitro; Cyclization; Structure activity relation; (R)-De-O-methyllasiodiplodin; Bicyclic compound; Affinity; Aromatic compound; Property structure relationship; Chemical synthesis; Acylate; Non steroid compound; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.12.101

Macrolide ( R)-de- O-methyllasiodiplodin ( 1), discovered to be a potent nonsteroidal antagonist of the mineralocorticoid receptor (MR), was synthesized via an efficient method and evaluated for MR antagonistic activity together with its analogs. Among all the tested compounds, compounds 18a, 18b and 18c, exhibited more potent antagonistic activity against MR with IC 50 values ranging from 0.58 to 1.11 μM. Generally, it was obviously demonstrated that acetylation at phenolic hydroxyl groups and the ring size in analogs of 1 were very important for MR antagonist activity.